Cocaine-dependence is a prevalent health problem with serious medical, psychological and societal deleterious effects. The understanding of the effects of cocaine use on the central nervous system could inform efforts towards treatment and rehabilitation of this serious disorder. Transcranial magnetic stimulation (TMS) provides a unique opportunity to non-invasively examine the inhibitory-excitatory states of the cerebral cortex in awake humans. This application is developed to examine TMS-based measures of cortical excitability in abstinent cocaine-dependent individuals. The proposed studies will also probe the physiological correlates of cocaine-induced paranoid states. Our main hypothesis is that decreased cortical excitability in cocaine-dependent subjects reflects a protective mechanism mediated mainly via increased neuronal membrane stability. We plan to demonstrate that decreased cortical excitability in cocaine-dependent subjects is mediated mainly via cellular membrane ion transport mechanisms as reflected in measurement of TMS-generated motor thresholds. In addition to a healthy control group, a healthy but at-risk for cocaine-dependence group will be examined to ascertain if genetic predisposition plays a role in the TMS findings. We further plan to demonstrate significant prolongation of the TMS-induced cortical silent period and increased intra-cortical inhibition as measured via paired-pulse stimulation techniques, in subjects with history of cocaine-induced paranoia (CIP) as compared to cocaine-dependent subjects without such a history. Our third specific aim is to examine the correlation between TMS-based measures of cortical inhibition and sensory gating measures of cerebral inhibition (also have been shown to be abnormal in this population). An additional exploratory aim is to probe the personality correlates of TMS-based cortical excitability changes in cocaine-dependent subjects. [unreadable] [unreadable] [unreadable]